Solution of the Multiple-Constraint Allocation Problem Using Recursive Search Dynamic Programming

Engineerin

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Policy dynamics and types of agency : From individual to collective patterns of action

\u6458\u8981 \u9664\u53bb\u4e0e\u7ed3\u6784\u7684\u76f8\u5173\u6027, \u548c\u5bf9\u51b3\u7b56\u7ed3\u679c\u7684\u9650\u5236\u6027, \u80fd\u52a8\u6027(agency) \u8fd8\u662f\u63cf\u8ff0\u653f\u7b56\u52a8\u6001\u7684\u4e00\u4e2a\u5173\u952e \u56e0\u7d20\u3002\u7684\u786e, \u80fd\u52a8\u6027\u8fd9\u4e00\u6982\u5ff5\u53ef\u80fd\u4f1a\u6839\u636e\u7ecf\u9a8c\u53c2\u8003\u548c\u653f\u7b56\u80cc\u666f\u800c\u5305\u542b\u4e0d\u540c\u6210\u5206\u3002\u5728\u653f\u7b56\u7814\u7a76 \u4e2d, \u4e0d\u540c\u80fd\u52a8\u8005\u88ab\u6982\u5ff5\u5316\u800c\u5728\u51b3\u7b56\u4e2d\u5177\u6709\u76f8\u5173\u6027, \u4f46\u4ed6\u4eec\u5904\u7406\u7684\u5374\u662f\u76f8\u4f3c\u4e2a\u4f53\u7684\u95ee\u9898\u3002\u8fd9\u4e9b\u4e2a \u4f53\u65e0\u5e8f\u5730\u53c2\u4e0e\u5230\u653f\u7b56\u8fc7\u7a0b\u4e2d, \u505a\u51fa\u7279\u5b9a\u7684\u8d21\u732e\u3002\u672c\u6587\u4e3b\u5f20\u2014\u4e0d\u540c\u7c7b\u578b\u7684\u80fd\u52a8\u8005\u53ef\u88ab\u5f52\u56e0\u4e3a\u7279\u5b9a \u884c\u52a8\u6a21\u5f0f\u7684\u7ed3\u679c, \u5176\u76f8\u5173\u4efb\u52a1\u662f\u653f\u7b56\u52a8\u6001\u4e2d\u7a33\u5b9a\u6027\u548c\u53d8\u5316\u7684\u5fc5\u9700\u6210\u5206\u2014\u8fdb\u800c\u63d0\u51fa\u5c06\u653f\u7b56\u52a8\u6001\u4e2d \u7684\u80fd\u52a8\u6027\u8fdb\u884c\u201c\u53bb\u4eba\u683c\u5316\u201d (de-personalize)\u3002\u7531\u6b64, \u672c\u6587\u63d0\u51fa\u4e09\u79cd\u6a21\u5f0f\u7c7b\u578b\u2014\u4f01\u4e1a\u5bb6\u7cbe\u795e\u578b\u3001\u7ecf \u7eaa\u4eba\u578b\u548c\u9886\u5bfc\u529b\u578b\u2014\u540c\u65f6\u5c55\u793a\u4e86\u5728\u653f\u7b56\u52a8\u6001\u4e2d\u8fd0\u7528\u8fd9\u4e9b\u6982\u5ff5\u5982\u4f55\u80fd\u66f4\u597d\u5730\u5b89\u6392\u3001\u63cf\u8ff0\u548c\u628a\u63e1\u80fd \u52a8\u6027\u3002Despite the relevance of structures and constraints to the outcomes of policy\u2010making, agency emerges as a key aspect in accounting for policy dynamics. Indeed, agency is a concept that may embrace different components according to their empirical reference and policy context. In policy studies, different agents are conceptualized to be relevant in policy\u2010making, but they address the issues of similar individuals who randomly jump into the policy process to make a specific contribution. This paper proposes to de\u2010personalize agency in policy dynamics by arguing that the different types of agents can be attributed to specific patterns of action and that related tasks are a necessary element of stability and change in policy dynamics. Thus, we propose three types of patterns\u2014entrepreneurship, brokerage, and leadership\u2014and we show how the use of these concepts can help to better order, describe, and grasp agency in policy dynamics.A pesar de la relevancia de las estructuras y limitaciones de los resultados de la creacion de pol\u131ticas, la autonom\u131a surge como un aspecto clave de la contabilidad para la de pol\u131ticas. En efecto, la autonom\u131a es un concepto que puede incluir diferentes componentes de acuerdo con su referencia emp\u131rica y el contexto pol\u131tico. En los estudios pol\u131ticos hay diferentes agentes que estan conceptualizados como relevantes para la creacion de pol\u131ticas, pero abordan los temas de individuos similares que entran al proceso pol\u131tico al azar para contribuir de una forma espec\u131fica. Este documento propone despersonalizar la autonom\u131a en la dinamica de pol\u131ticas al argumentar que los diferentes tipos de agentes pueden ser atribuidos a patrones espec\u131ficos de accion y que las tareas relacionadas son un elemento necesario de estabilidad y cambio en la dinamica pol\u131tica. Por ende, proponemos tres tipos de patrones\u2014emprendimiento, intermediacion y liderazgo\u2014y mostramos como el uso de estos conceptos puede ayudar a organizar, describir y entender mejor la autonom\u131a en la dinamica de pol\u131ticas